title: Analysis of Gpr126 function defines distinct mechanisms controlling the initiation and maturation of myelin.
abstract: In peripheral nerves, Schwann cells form the myelin sheath, which allows the efficient propagation of action potentials along axons. The transcription factor Krox20 regulates the initiation of myelination in Schwann cells and is also required to maintain mature myelin. The adhesion G protein-coupled receptor (GPCR) Gpr126 is essential for Schwann cells to initiate myelination, but previous studies have not addressed the role of Gpr126 signaling in myelin maturation and maintenance. Through analysis of Gpr126 in zebrafish, we define two distinct mechanisms controlling the initiation and maturation of myelin. We show that gpr126 mutant Schwann cells elaborate mature myelin sheaths and maintain krox20 expression for months, provided that the early signaling defect is bypassed by transient elevation of cAMP. At the onset of myelination, Gpr126 and protein kinase A (PKA) function as a switch that allows Schwann cells to initiate krox20 expression and myelination. After myelination is initiated, krox20 expression is maintained and myelin maturation proceeds independently of Gpr126 signaling. Transgenic analysis indicates that the Krox20 cis-regulatory myelinating Schwann cell element (MSE) becomes active at the onset of myelination and that this activity is dependent on Gpr126 signaling. Activity of the MSE declines after initiation, suggesting that other elements are responsible for maintaining krox20 expression in mature nerves. We also show that elevated cAMP does not initiate myelination in the absence of functional Neuregulin 1 (Nrg1) signaling. These results indicate that the mechanisms regulating the initiation of myelination are distinct from those mediating the maturation and maintenance of myelin.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Glenn
authors.forename: William S
authors.initials: WS
authors.lastname: Talbot
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018734:Genes, erbB-2; D053403:Lateral Line System / Q000196:embryology / Q000502:physiology; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000502:physiology / Q000648:ultrastructure; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497329:EGR2 protein, Xenopus; D051767:Early Growth Response Protein 2; D004676:Myelin Basic Protein; D020890:Neuregulin-1; D043562:Receptors, G-Protein-Coupled; D029961:Zebrafish Proteins; C543742:stx7l protein, zebrafish; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Myelination; Schwann cells; Zebrafish